Recent developments and current status of gene therapy using viral vectors in the United Kingdom
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《英国医生杂志》
1 Department of Oncology, St George's Hospital Medical School, London SW17 0RE, 2 Institute Cancer Research, London SW7 0RP
Correspondence to: H Pandha hpandha@sghms.ac.uk
Introduction
We searched Medline and Google, using the terms "gene therapy" and "viral vectors." We also studied the websites www.wiley.co.uk/genmed/clinical and www.advisorybodies.doh.gov.uk/genetics/gtac for information on ongoing trials using viral vectors in the United Kingdom.
Viral gene therapy: successes and failures
Despite these recent reports, the field of gene therapy has come a very long way over the past decade. Gene transfer efficiencies have improved, and many new vectors are in preclinical studies. Viral vectors remain the gene transfer vehicles of choice for clinical trials in the United Kingdom and worldwide. Table 1 shows clinical trials in the United Kingdom that are open and ongoing. Of all 88 UK trials registered with GTAC, 75% (66) entail the use of viral vectors; most of these are for the treatment of cancer.
Table 1 Ongoing clinical trials in the United Kingdom, March 2004 (sources: website of Journal of Gene Medicine, www.wiley.co.uk/genmed/clinical; and of Gene Therapy Advisory Committee www.advisorybodies.doh.gov.uk/genetics/gta)
Adenoviral vectors
Retroviral vectors are being used in a range of clinical trials across the United Kingdom. One of the advantages of using retroviruses is their ability to integrate into the genome and maintain expression for long periods of time. However, given recent reports, the risk of oncogenesis induced by retroviral integration is clearly higher than thought previously. These risks must therefore be reduced by strategies such as targeting integration to inactive regions of the host genome.8 One approach could be to use the site specific integration machinery of bacteriophage C31, which has recently been used in non-viral delivery approaches to achieve targeted integration in mouse and human cells.9
Replication competent viral vectors
Despite the X-SCID and Gelsinger cases no serious adverse events have so far been reported in gene therapy trials in the United Kingdom. This is at least in part due to the small numbers of patients treated. It is important that lessons are learnt from these cases and that they are used to improve our understanding of vector biology and pharmacology. Although GTAC has a central role in controlling gene therapy studies in the United Kingdom, calls have materialised for a harmonisation of legislation among European states and between Europe and the United States.11 Clearly, more efforts are needed to improve vectors to prevent the risk of insertional mutagenesis and also to direct the expression of therapeutic genes to specific tissues using both transcriptional and transductional targeting. This, in turn, will reduce vector doses and potentially immunogenicity.
Additional educational resources
Review articles
Cavazzana-Calvo M, Thrasher A, Mavilio F. The future of gene therapy. Nature 2004;427: 779-81.
Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nature Rev Genet 2003;4: 346-58.
Lundstrom K. Latest development in viral vectors for gene therapy. Trends Biotechnol 2003;213: 117-22.
Useful sources of information and their websites
Journal of Gene Medicine (www.wiley.co.uk/genmed/clinical)—Contains information on all completed and ongoing clinical trials worldwide
Gene Therapy Advisory Committee (www.advisorybodies.doh.gov.uk/genetics/gtac)—Contains information on all completed and ongoing clinical trials in the United Kingdom
Information for patients
www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml—Contains basic information on gene therapy and links to other websites
Cancer BacUp (www.cancerbacup.org.uk—Contains information on all types of cancers as well as information on gene therapy trials for cancer
Despite the setbacks successes have been achieved. Of the 18 SCID patients treated for their life threatening condition, 17 are still alive and have had a healthy, functioning immune system for up to five years and a good quality of life. In addition to monogenic conditions, gene therapy also represents a viable treatment for multigenic disorders, such as cancer, either as a standalone treatment or in combination with chemotherapy or radiotherapy. A huge amount of work is yet to be done, but with efficient monitoring of trials and continuous improvements of viral vectors, gene therapy may still represent an important addition to the treatment armamentarium for a range of diseases.
Contributors: HP was responsible for proposing the article, for critical reading, and for approval of the final manuscript. He is the guarantor. KR was responsible for researching and writing the article. KH was responsible for critical reading and advising on the article.
Funding: None.
Competing interests: None declared.
References
BBC Online News. "Bubble boy" saved by gene therapy. 3 April 2002, http://news.bbc.co.uk/1/hi/health/1906999.stm (accessed 20 Aug 2004).
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000;288: 669-72:
Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296: 2410-3..
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302: 415-9.
Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nature Genet 2000;24: 257-61.
Lehrman S. Virus treatment questioned after gene therapy death. Nature 1999;401: 517-8.
Kay MA, Nakai H. Looking into the safety of AAV vectors. Nature 2003;424: 251.
Bushman F. Targeting retroviral integration. Mol Ther 2000; 6.
Olivares EC, Hollis RP, Chalberg TW, Meuse L, Kay MA, Calos MP. Site-specific genomic integration produces therapeutic factor IX levels in mice. Nature Biotech 2002;20: 1124-8.
Ries, S and Kirn, W M. ONYX-015: mechanisms of action and clinical potential of a replication selective adenovirus. Br J Cancer 2002;86: 5-11.
Cavazzana-Calvo M, Thrasher A, Mavilio F. The future of gene therapy. Nature 2004;427: 779-81.(Kate Relph, scientific wr)
Correspondence to: H Pandha hpandha@sghms.ac.uk
Introduction
We searched Medline and Google, using the terms "gene therapy" and "viral vectors." We also studied the websites www.wiley.co.uk/genmed/clinical and www.advisorybodies.doh.gov.uk/genetics/gtac for information on ongoing trials using viral vectors in the United Kingdom.
Viral gene therapy: successes and failures
Despite these recent reports, the field of gene therapy has come a very long way over the past decade. Gene transfer efficiencies have improved, and many new vectors are in preclinical studies. Viral vectors remain the gene transfer vehicles of choice for clinical trials in the United Kingdom and worldwide. Table 1 shows clinical trials in the United Kingdom that are open and ongoing. Of all 88 UK trials registered with GTAC, 75% (66) entail the use of viral vectors; most of these are for the treatment of cancer.
Table 1 Ongoing clinical trials in the United Kingdom, March 2004 (sources: website of Journal of Gene Medicine, www.wiley.co.uk/genmed/clinical; and of Gene Therapy Advisory Committee www.advisorybodies.doh.gov.uk/genetics/gta)
Adenoviral vectors
Retroviral vectors are being used in a range of clinical trials across the United Kingdom. One of the advantages of using retroviruses is their ability to integrate into the genome and maintain expression for long periods of time. However, given recent reports, the risk of oncogenesis induced by retroviral integration is clearly higher than thought previously. These risks must therefore be reduced by strategies such as targeting integration to inactive regions of the host genome.8 One approach could be to use the site specific integration machinery of bacteriophage C31, which has recently been used in non-viral delivery approaches to achieve targeted integration in mouse and human cells.9
Replication competent viral vectors
Despite the X-SCID and Gelsinger cases no serious adverse events have so far been reported in gene therapy trials in the United Kingdom. This is at least in part due to the small numbers of patients treated. It is important that lessons are learnt from these cases and that they are used to improve our understanding of vector biology and pharmacology. Although GTAC has a central role in controlling gene therapy studies in the United Kingdom, calls have materialised for a harmonisation of legislation among European states and between Europe and the United States.11 Clearly, more efforts are needed to improve vectors to prevent the risk of insertional mutagenesis and also to direct the expression of therapeutic genes to specific tissues using both transcriptional and transductional targeting. This, in turn, will reduce vector doses and potentially immunogenicity.
Additional educational resources
Review articles
Cavazzana-Calvo M, Thrasher A, Mavilio F. The future of gene therapy. Nature 2004;427: 779-81.
Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nature Rev Genet 2003;4: 346-58.
Lundstrom K. Latest development in viral vectors for gene therapy. Trends Biotechnol 2003;213: 117-22.
Useful sources of information and their websites
Journal of Gene Medicine (www.wiley.co.uk/genmed/clinical)—Contains information on all completed and ongoing clinical trials worldwide
Gene Therapy Advisory Committee (www.advisorybodies.doh.gov.uk/genetics/gtac)—Contains information on all completed and ongoing clinical trials in the United Kingdom
Information for patients
www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml—Contains basic information on gene therapy and links to other websites
Cancer BacUp (www.cancerbacup.org.uk—Contains information on all types of cancers as well as information on gene therapy trials for cancer
Despite the setbacks successes have been achieved. Of the 18 SCID patients treated for their life threatening condition, 17 are still alive and have had a healthy, functioning immune system for up to five years and a good quality of life. In addition to monogenic conditions, gene therapy also represents a viable treatment for multigenic disorders, such as cancer, either as a standalone treatment or in combination with chemotherapy or radiotherapy. A huge amount of work is yet to be done, but with efficient monitoring of trials and continuous improvements of viral vectors, gene therapy may still represent an important addition to the treatment armamentarium for a range of diseases.
Contributors: HP was responsible for proposing the article, for critical reading, and for approval of the final manuscript. He is the guarantor. KR was responsible for researching and writing the article. KH was responsible for critical reading and advising on the article.
Funding: None.
Competing interests: None declared.
References
BBC Online News. "Bubble boy" saved by gene therapy. 3 April 2002, http://news.bbc.co.uk/1/hi/health/1906999.stm (accessed 20 Aug 2004).
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000;288: 669-72:
Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296: 2410-3..
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302: 415-9.
Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nature Genet 2000;24: 257-61.
Lehrman S. Virus treatment questioned after gene therapy death. Nature 1999;401: 517-8.
Kay MA, Nakai H. Looking into the safety of AAV vectors. Nature 2003;424: 251.
Bushman F. Targeting retroviral integration. Mol Ther 2000; 6.
Olivares EC, Hollis RP, Chalberg TW, Meuse L, Kay MA, Calos MP. Site-specific genomic integration produces therapeutic factor IX levels in mice. Nature Biotech 2002;20: 1124-8.
Ries, S and Kirn, W M. ONYX-015: mechanisms of action and clinical potential of a replication selective adenovirus. Br J Cancer 2002;86: 5-11.
Cavazzana-Calvo M, Thrasher A, Mavilio F. The future of gene therapy. Nature 2004;427: 779-81.(Kate Relph, scientific wr)